CD40, also referred to as tumor necrosis factor receptor superfamily member 5 or TNFR5, is a transmembrane costimulatory protein expressed on antigen presenting cells such as B cells, macrophages, and dendritic cells. Binding of this protein with CD40L (CD154), the major ligand expressed primarily by activated T lymphocytes and platelets, activates antigen presenting cells and triggers a variety of downstream signalings, including immune cell activation and proliferation, and production of cytokines and chemokines, enhancing cellular and immune functions (Ara A et al, (2018)Immunotargets Ther 7: 55-61).
On the other hand, CD40 is also found on non-immune cells and tumors (Costello et al., (1999) Immunol Today 20(11): 488-493; Tong et al., (2003) Cancer Gene Ther 10(1): 1-13; Lee et al., (2014) Curr Cancer Drug Targets 14(7): 610-620; Ara A et al, (2018) supra), and was reported to be involved in pathologies of several inflammatory diseases, including autoimmune diseases, atherothrombosis, cancers, and respiratory diseases. For example, CD40/CD40L expression was up-regulated in atheroma-associated cells. CD40 was found in nearly all B-cell malignancies and up to 70% of solid tumors, and CD40 engagement in certain B-cell malignancies caused increased expression of many factors that protect the cell from apoptosis induced by apoptotic agents (Lee et al., (1999) Proc Natl Acad Sci USA 96:9136-9141).
Despite of CD40's complicated effects on tumor development, several anti-CD40 antibodies have been developed for potential tumor treatment. CP-870,893, a fully human IgG2 CD40 agonistic antibody developed by Pfizer, can activate dendritic cells and has shown clinical efficacy in a number of settings of patients with advanced cancers (Vonderheide et al., (2007) J Clin Oncol 25(7): 876-883; Gladue et al., (2011) Cancer Immunol Immunother 60(7): 1009-1017; Beatty et al., (2013) Expert Rev Anticancer Ther 17(2): 175-186; Vonderheide et al., (2013) Oncoimmunology 2(1): e23033; Nowak et al., Ann Oncol 26(12): 2483-2490; 2015 U.S. Pat. No. 7,338,660). Dacetuzumab, also known as SGN-40, a humanized IgG1 agonistic anti-CD40 antibody developed by Seattle Genetics, has also shown anti-tumor activity when given intravenously every week, especially in patients with diffuse large B-cell lymphoma. Preclinical data also showed synergic effect of Dacetuzumab with other agents such as the anti-CD20 mAb rituximab (Lapalombella et al., (2009) Br J Haematol 144(6): 848-855; Hussein et al., (2010) Haematologica 95(5): 845-848; de Vos et al., (2014) J Hematol Oncol 7: 44). Chi Lob 7/4, another chimeric anti-human IgG1 agonistic anti-CD40 antibody developed by Cancer Research UK, is undergoing initial clinical testing. Eleven of the 21 patients showed stable disease with no complete or partial responses (Chowdhury et al., (2014) Cancer Immunol Res 2(3): 229-240). Further, antagonistic anti-CD40 antibodies have been studied for their anti-tumor activity on human multiple myeloma and chronic lymphocytic leukemia (Bensinger W et al., (2012) Br J Haematol. 159(1): 58-66; Mohammad Luqman et al., (2008) Blood 112: 711-720).
There remains a need for more CD40 antibodies with improved pharmaceutical characteristics.